Application of Computational Techniques in Pharmacy and Medicine

556 Pages·2014·17.04 MB·English

by  Leonid Gorb

Challenges and Advances in Computational
Chemistry and Physics
Volume 17
Series Editor
Jerzy Leszczynski
Jackson State University, Jackson, Mississippi, USA
This book series provides reviews on the most recent developments in computation-
al chemistry and physics. It covers both the method developments and their applica-
tions. Each volume consists of chapters devoted to the one research area. The series
highlights the most notable advances in applications of the computational methods.
The volumes include nanotechnology, material sciences, molecular biology, struc-
tures and bonding in molecular complexes, and atmospheric chemistry. The authors
are recruited from among the most prominent researchers in their research areas.
As computational chemistry and physics is one of the most rapidly advancing sci-
entific areas such timely overviews are desired by chemists, physicists, molecular
biologists and material scientists. The books are intended for graduate students and
researchers.
More information about this series at http://www.springer.com/series/6918
Leonid Gorb • Victor Kuz’min • Eugene Muratov
Editors
Application of Computational
Techniques in Pharmacy
and Medicine
Editors
Leonid Gorb Eugene Muratov
Department of Molecular Biophysics Department of Chemical Biology
Laboratory of Computational and Medicinal Chemistry
Structural Biology University of North Carolina, Laboratory
Kiev for Molecular Modeling
Ukraine Chapel Hill
North Carolina
Victor Kuz’min USA
Department of Molecular Structure
and Chemoinformatics
A.V. Bogatsky Physical-Chemical Institute,
National Academy of Sciences
of Ukraine
Odessa
Ukraine
ISBN 978-94-017-9256-1 ISBN 978-94-017-9257-8 (eBook)
DOI 10.1007/978-94-017-9257-8
Springer Dordrecht Heidelberg New York London
Library of Congress Control Number: 2014952367
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Preface
Advances in computer hardware parallel by recent enormous progress in develop-
ing computer algorithms that utilize hundreds and even thousand of computer nodes
made applications of computational techniques to be indispensable in scientific re-
search and fundamental science applications. Such research areas as computational
biology, molecular pharmacy and molecular medicine are certainly among those
where these computational applications are actively introduced. As the result, mod-
ern multiprocessor computers are able to treat real-life biological systems consist-
ing of millions of atoms (ribosoms, nucleosoms, or even viruses) in a time frame of
hundred nanoseconds. This tendency manifests itself even more clearly in the area
of bioinformatics. Nowadays, combinatorial and high–throughput screening (HTS)
technologies are widely used in both academia and industry. The pharmaceutical
companies run the HTS platforms, incorporating libraries of several millions of
compounds. Also, there are more and more academic centers that conduct HTS
and integrate their platform with industrial drug discovery centers. Therefore, one
can safely say that the computational chemist has become a respectable member of
a drug design community, playing the same role as the synthetic or pharmacolo-
gists chemists. More and more often such projects have interdisciplinary character
presenting an interplay between the theory and the experiment. They are intended
to provide basic information as well as the data which could be used in practical
pharmacological and medical applications.
The proposed volume provides basic information as well as the details of com-
putational and computational-experimental studies improving our knowledge on
functioning of alive, different properties of drugs, and predictions of new medi-
cines. Whenever it is possible the interplay between the theory and the experiment
is provided. The unique feature of the book is the fact that such different in prin-
ciples computational techniques as quantum-chemical and molecular dynamic ap-
proaches on one hand and quantitative structure–activity relationships on another
hand are considered inside one volume. The reviews presented in the volume cover
main tendencies and priorities in application of computational methods of quantum
chemistry, molecular dynamics and chemoinformatics to solve the tasks of phar-
macy and medicine.
v
vi Preface
The present book is aimed at a relatively broad readership that includes advanced
undergraduate and graduate students of chemistry, physics and engineering, post-
doctoral associates and specialists from both academia and industry who carry out
research in the fields that require molecular and QSA(P)R modeling. This book
could also be useful to students in biochemistry, structural biology, bioengineering,
bioinformatics, pharmaceutical chemistry, as well as other related areas, who have
an interest in molecular-level computational techniques.
The book starts from the reviews that describe the studies of biological systems
which are performed by the methods of quantum chemistry and classical molecu-
lar dynamics. The two initial chapters describe the theory and application of such
methods as hybrid quantum-mechanical/molecular mechanical approximation,
Monte-Carlo, molecular docking and molecular dynamics, in conjunction with the
application of experimental techniques as Infra-Red, Raman, UV-VIS spectros-
copies, and microcalorimetry. Next four chapters continue to describe the current
status of the investigations in such vital area as functioning of DNA. It covers for-
mation of DNA lesions, computational rational design of DNA polymerase inhibi-
tors, modeling the structure of DNA quadruplexes, and the study on the structure,
relative stability, and proton affinities of such building blocks as nucleotides. The
seventh, eighth, ninth and tenth chapters are devoted to the application of compu-
tational and experimental techniques in such areas of medical and pharmaceutical
chemistry as enzyme-inhibitor interactions, interaction of enzymes with biological
membranes and a probe of polyphenol glycosides as potential remedies in kidney
stones therapy and transformations of epoxided in vivo and in vitro. The following
six reviews describe the advantages in the area of chemoinformatics. Most of them
are devoted to developing and applications of the QSAR methodology to predict
an activity and design of novel biologically active compounds. In particular, the
criteria for correct QSAR models, their opprtunities and limitations are studied in
the eleventh chapter. Very original QSAR methodoly named MICROCOSM is pre-
sented in chapter twelfth. The chapters 11th, 13th and 14th devoted to analysis such
important properties of biologivally active compounds (possible drugs) as toxicity
and farmokinetics. Very interesting methodology which combines molecular dy-
namics and docking approaches is described in the 15th chapter. The book is clos-
ing up by the 16th chapter which describes modern state of chemoinformatics, new
problems and perspectives of treatment of avalanche-like amount of experimental
chemical and biological information.
The editors of this book gratefully thank all the authors for their time and con-
tribution. We hope that this volume may give the reader (both in academia and in
an industrial pharmaceutical community) a useful overview of the computational
and experimental techniques that are currently in use in the areas of computational
pharmacy and medicine.
May, 2014 Leonid Gorb
Victor Kuz’min
Eugene Muratov
Contents
1 Hybrid QM/MM Methods: Treating Electronic Phenomena
in Very Large Molecular Systems ........................................................... 1
Antonio Monari and Xavier Assfeld
2 Structure, Thermodynamics and Energetics of Drug-DNA
Interactions: Computer Modeling and Experiment ............................. 21
Maxim P. Evstigneev and Anna V. Shestopalova
3 Formation of DNA Lesions, its Prevention and Repair ........................ 59
Nihar R. Jena, Neha Agnihotri and Phool C. Mishra
4 DNA Dependent DNA Polymerases as Targets
for Low-Weight Molecular Inhibitors: State of Art
and Prospects of Rational Design ........................................................... 95
Alexey Yu. Nyporko
5 Molecular Structures, Relative Stability, and Proton
Affinities of Nucleotides: Broad View and Novel Findings .................. 137
Tetiana A. Zubatiuk, Gennady V. Palamarchuk, Oleg V. Shishkin,
Leonid Gorb and Jerzy Leszczynski
6 Quantum Chemical Approaches in Modeling the Structure
of DNA Quadruplexes and Their Interaction with Metal Ions
and Small Molecules ................................................................................ 181
Mykola Ilchenko and Igor Dubey
7 D ensity Functional Theory Calculations of Enzyme–Inhibitor
Interactions in Medicinal Chemistry and Drug Design........................ 207
Alexander B. Rozhenko
vii
viii Contents
8 Molecular Dynamics Simulations of Lipid Bilayers
with Incorporated Peptides ..................................................................... 241
Milan Melicherčík, Tibor Hianik and Ján Urban
9 Polyphenol Glycosides as Potential Remedies in Kidney
Stones Therapy. Experimental Research Supported
by Computational Studies ....................................................................... 271
D. Toczek, E. Klepacz, S. Roszak and R. Gancarz
10 Q uantum-Chemical Investigation of Epoxidic Compounds
Transformation. Application for In Vitro and In Vivo
Processes Modeling .................................................................................. 295
Sergiy Okovytyy
11 Computational Toxicology in Drug Discovery: Opportunities
and Limitations......................................................................................... 325
Alexey Zakharov and Alexey Lagunin
12 C onsensus Drug Design Using It Microcosm ........................................ 369
Pavel M. Vassiliev, Alexander A. Spasov, Vadim A. Kosolapov,
Aida F. Kucheryavenko, Nataliya A. Gurova and Vera A. Anisimova
13 C ontinuous Molecular Fields Approach Applied
to Structure-Activity Modeling ............................................................... 433
Igor I. Baskin and Nelly I. Zhokhova
14 Q uantitative Structure-Property Relationship Analysis of Drugs’
Pharmacokinetics Within the Framework of Biopharmaceutics
Classification System Using Simplex Representation of Molecular
Structure ................................................................................................... 461
N. Ya. Golovenko, I. Yu. Borisyuk, М. А. Kulinskiy, P. G. Polishchuk,
E. N. Мuratov and V. Е. Kuz’min
15 ( How to) Profit from Molecular Dynamics-based
Ensemble Docking .................................................................................... 501
Susanne von Grafenstein, Julian E. Fuchs and Klaus R. Liedl
16 C heminformatics: At the Crossroad of Eras ......................................... 539
Denis Fourches
Index ................................................................................................................ 547
Contributors
Neha Agnihotri Department of Chemistry, University of Saskatchewan, Saskatoon,
Canada
Vera A. Anisimova Institute of Physical and Organic Chemistry at Southern
Federal University (IPOC SFU), Rostov-on-Don, Russian Federation
Xavier Assfeld Université de Lorraine, Nancy, France
Igor I. Baskin Faculty of Physics, M. V. Lomonosov Moscow State University,
Moscow, Russia
I. Yu. Borisyuk A.V. Bogatsky Physico-Chemical Institute NAS of Ukraine,
Odessa, Ukraine
Igor Dubey Institute of Molecular Biology and Genetics, National Academy of
Sciences of Ukraine, Kyiv, Ukraine
Maxim P. Evstigneev Sevastopol National Technical University (SevNTU),
Sevastopol, Ukraine
Belgorod State University (BGU), Belgorod, Russia
Denis Fourches Laboratory for Molecular Modeling, University of North Carolina,
Chapel Hill, NC, USA
Julian E. Fuchs Institute of General, Inorganic and Theoretical Chemistry,
University of Innsbruck, Innsbruck, Austria
R. Gancarz Organic and Pharmaceutical Technology Group, Chemistry
Department, Wrocław University of Technology (WUT), Wrocław, Poland
Susanne von Grafenstein Institute of General, Inorganic and Theoretical
Chemistry, University of Innsbruck, Innsbruck, Austria
N. Ya. Golovenko A.V. Bogatsky Physico-Chemical Institute NAS of Ukraine,
Odessa, Ukraine
ix